Submissions for variant NM_000257.4(MYH7):c.1331A>G (p.Asn444Ser)

dbSNP: rs730880159

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158797	SCV000208732	likely pathogenic	not provided	2015-07-07	criteria provided, single submitter	clinical testing	p.Asn444Ser (AAT>AGT): c.1331 A>G in exon 14 of the MYH7 gene (NM_000257.2). The N444S mutation in the MYH7 gene has been reported in one Italian individual diagnosed with HCM and was absent in 384 chromosomes from healthy, Italian control individuals in this study (Roncarti R et al., 2011). Mutations in nearby residues (R442C, R442H, I443T, K450E, K450T) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Furthermore, N444S was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, N444S in the MYH7 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s).
Blueprint Genetics	RCV000208202	SCV000264078	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2015-04-07	criteria provided, single submitter	clinical testing
Invitae	RCV000468249	SCV000546228	pathogenic	Hypertrophic cardiomyopathy	2023-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 444 of the MYH7 protein (p.Asn444Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 21302287, 24704860; Invitae). ClinVar contains an entry for this variant (Variation ID: 181343). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, University of Leuven	RCV000468249	SCV000886832	uncertain significance	Hypertrophic cardiomyopathy	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381517	SCV002690322	uncertain significance	Cardiovascular phenotype	2019-09-06	criteria provided, single submitter	clinical testing	The p.N444S variant (also known as c.1331A>G), located in coding exon 12 of the MYH7 gene, results from an A to G substitution at nucleotide position 1331. The asparagine at codon 444 is replaced by serine, an amino acid with highly similar properties, and is located in the head domain. This variant has been detected in an individual with hypertrophic cardiomyopathy (HCM) (Roncarati R et al. J. Cell. Physiol., 2011 Nov;226:2894-900), and has also been detected in additional individuals from HCM cohorts; however clinical details were limited, and case reports may overlap (Captur G et al. Circ Cardiovasc Genet, 2014 Jun;7:241-8; Homburger JR et al. Proc. Natl. Acad. Sci. U.S.A., 2016 06;113:6701-6; Ho CY et al. Circulation, 2018 Oct;138:1387-1398). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.